Human Pancreatic Cancer Tumors Are Nutrient Poor and Tumor Cells Actively Scavenge Extracellular Protein

Abstract

Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiological albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids, and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC.

The redox requirements of proliferating mammalian cells

“…However, amino acid concentrations may be reduced in other fluids, limiting their availability to cells. In this context, acquiring amino acids from protein in the extracellular environment represents another source of amino acids (31)(32)(33).…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…In vitro, it is rather dif fi cult to ap pre ci ate this com plex ity, be cause of the lack of het ero gene ity, both meta bolic [5] and cel lu lar [251], but also be cause of the lack of en vi ron men tal clues [8], as well as cel lu lar po lar iza tion [255]. The re quire ment of grow ing cells in vitro with con cen tra tion of glu cose far ex ceed ing the phys i o log i cal lev els also leads to spe cific meta bolic adap ta tions [256][257][258]. While the cur rent cell cul ture con di tions are mostly aimed at al low ing cel lu lar pro lif er a tion at a dou bling rate gen er ally higher than 24 h, it is now nec es sary to de velop more ac cu rate cell cul ture con di tions to mimic nu tri ent con di tions re ca pit u lat ing the tu mor mi lieu [256].…”

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

“…When challenged with changes in the environment such as nutrient limitation or hypoxia, different tissues can engage adaptive metabolic programs, such as lipid and protein scavenging (24,25,35) to compensate, and these responses also contribute to the metabolic identity of normal and disease tissues. Metabolic flexibility, however, is not infinite, and extreme or prolonged changes in nutrient availability or intrinsic limitations of the cell to adapt to stress will constrain metabolism in all cells.…”